The present disclosure relates to inhibitors of c-Jun N-terminal kinases (JNKs). The disclosure also provides pharmaceutical compositions comprising the inhibitors of the present disclosure and methods of utilizing those compositions in the treatment of various disorders, such as Alzheimer's disease.
Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the extracellular signal regulated kinases (ERKs), the p38 MAP kinases and the c-Jun N-terminal kinases (JNKs). MAP kinases (MAPKs) are serine/threonine kinases and are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents. MAPKs phosphorylate various substrates including transcription factors, which in turn regulate the expression of specific genes.
Members of the JNK family are activated by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta), as well as by environmental stress, including UV irradiation, hypoxia, and osmotic shock (see, e.g., Minden et al., Biochemica et Biophysica Acta 1997, 1333:F85-F104). Three distinct JNK genes, jnk1, jnk2 and jnk3 were identified and at least ten different splicing isoforms exist in mammalian cells (see, e.g., Gupta et al., EMBO J. 1996, 15:2760-2770).
Down-stream substrates of JNKs include transcription factors c-Jun, ATF-2, Elk1, p53 and a cell death domain protein (DENN) (see, e.g., Zhang et al. Proc. Natl. Acad. Sci. USA 1998, 95:2586-2591). Each JNK isoform binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity in vivo (Gupta et al., supra).
JNKs have been implicated in mediating a number of physiological responses and disorders including cellular-response to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic targets related to activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, various cancers and neurodegenerative diseases.
Several reports have detailed the importance of JNK activation associated with liver disease or episodes of hepatic ischemia (see, e.g., Nat. Genet. 1999, 21:326-329; FEBS Lett. 1997, 420:201-204; J. Clin. Invest. 1998, 102:1942-1950; Hepatology 1998, 28:1022-1030). A role for JNK in cardiovascular disease such as myocardial infarction or congestive heart failure has also been reported (see, e.g., Circ. Res. 1998, 83:167-178; Circulation 1998, 97:1731-7). The JNK cascade also plays a role in T-cell activation, including activation of the IL-2 promoter (see, e.g., J. Immunol. 1999, 162:3176-87; Eur. J. Immunol. 1998, 28:3867-77; J. Exp. Med. 1997). A role for JNK activation in various forms of cancer has also been established. For example, constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis (Oncogene 1996, 13:135-42). JNK may play a role in Kaposi's sarcoma (KS) because it is thought that the proliferative effects of bFGF and OSM on KS cells are mediated by their activation of the JNK signaling pathway (see e.g., J. Clin. Invest. 1997, 99:1798-804). Other proliferative effects of certain cytokines implicated in KS proliferation, such as vascular endothelial growth factor (VEGF), IL-6 and TNF alpha, may also be mediated by JNK. In addition, regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, suggesting a role for JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) (see, e.g., Blood 1998, 92-2450-60).
While JNK1 and JNK2 are widely expressed in a variety of tissues, JNK3 is selectively expressed in the brain and, to a lesser extent, in the heart and testis (see, e.g., Gupta et al., supra; Mohit et al., Neuron 1995, 14:67-78; Martin et al., Brain Res. Mol. Brain. Res. 1996, 35:47-57). JNK3 has been linked to neuronal apoptosis induced by kainic acid, indicating a role of JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, JNK3 expression is localized to a subpopulation of pyramidal neurons in the CA1, CA4 and subiculum regions of the hippocampus and layers 3 and 5 of the neocortex (Mohit et al., supra). The CA1 neurons of patients with acute hypoxia showed strong nuclear JNK3-immunoreactivity compared to minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients (Zhang et al., supra). Thus, JNK3 appears to be involved in hypoxic and ischemic damage of CA1 neurons in the hippocampus.
Disruption of the JNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kainic acid, including the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the JNK3 signaling pathway is a critical component in the pathogenesis of glutamate neurotoxicity (Yang et al., Nature 1997, 389:865-870).
In addition, JNK3 co-localizes immunochemically with neurons vulnerable in Alzheimer's disease (Mohit et al., supra). Based on these findings, JNK signalling, especially that of JNK3, has been implicated in the areas of apoptosis-driven neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke.
Drug molecules that inhibit MAPKs, such as p38 are known (see, e.g., WO 98/27098 and WO 95/31451). However, inhibitors that are selective for JNKs versus other members of the MAPK family are rare (see, e.g., U.S. Patent Application Publication 20080033022). There is an unmet medical need for the development of potent, JNK specific inhibitors that are useful in treating the various conditions associated with JNK activation.